The focus of this application is to understand the brain mechanisms of persistence versus desistence of adolescent onset alcohol and/or marijuana use disorder (defined as DSM-IV substance abuse/dependence (SUD)) from adolescence into young adulthood. We propose to measure prefrontal and hippocampal cognitive function with a comprehensive neuropsychological battery and a functional MRI (fMRI) scan paradigm, the Decision-Reward Uncertainty Task, designed to challenge the two major subdivisions of prefrontal cortex (PFC), the dorsolateral (dlPFC) and ventromedial (vmPFC) systems. DlPFC and vmPFC serve distinct components of executive functions involved in decision making and reward evaluation, respectively. SUDs are associated with dysfunction in these PFC systems. The application builds on a unique longitudinal study of a representative population sample of children: the Great Smoky Mountains Study (GSMS). Participants (N=1,411 surviving) were first assessed for Axis I disorders including drug and alcohol use, abuse, and addiction in 1993 at ages 9-13, and have received an average of 6 assessments so far. Half the participants are female, and 25% of the sample is American Indian. Participants will be recruited from the GSMS, which re-assesses DSM-IV Axis I diagnosis at ages 26-28, and on the basis of which 160 will be recruited into a case-control study (40 in each cell): 1) adolescence-limited SUD (AL- SUD), 2) adolescent persistent also called life course persistent SUD (LCP -SUD), 3) a high risk for SUD group of young adults (high risk group) with a history of adolescent psychiatric disorders who do not have a history of SUDs and are age, sex, and sociodemographically matched to the SUD subjects, and 4) a control group with no history of SUD or major Axis I disorders. Neurobiological studies of an adolescent onset SUD need to control for co-morbidity since the PFC deficits seen in mental disorders may be responsible for the increased risk for SUD. We predict that there will be dlPFC and vmPFC functional differences in subjects with LCP-SUD vs. AL-SUD. This proposal will also allow us to measure the effects of an adolescent limited vs persistent SUD on young adult prefrontal and hippocampal structural and functional development. We expect that we will observe significant differences in the patterns of dlPFC and vmPFC activity, cognitive function, and hippocampal volumes between AL-SUD, LCP SUD, high risk, and control groups. PUBLIC HEALTH RELEVANCE Understanding the neurobiological underpinnings of individuals who go on to have lifelong problems with drugs and alcohol versus those who do not has important relevance to public health. This understanding can help to better identify those at risk and to help develop better treatments and deliver resources and interventions to these vulnerable individuals. Understanding of brain dysfunction of addiction is critical for more effective treatments of adolescent substance abuse.